It is now recognised that excitatory amino acids and more especially glutamate play a key role in the physiological processes of neuronal plasticity and in the mechanisms underlying learning and memory. Pathophysiological studies have clearly indicated that a deficit in glutamatergic neurotransmission is closely associated with the development of Alzheimer""s disease (Neuroscience and Biobehavioral reviews, 1992, 16, 13-24; Progress in Neurobiology, 1992, 39, 517-545).
Moreover, countless studies over recent years have shown the existence of excitatory amino acid receptor sub-types and of their functional interactions (Molecular Neuropharmacology, 1992, 2, 15-31).
Among those receptors, the AMPA receptor (xe2x80x9cxcex1-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acidxe2x80x9d) seems to be the most implicated in the phenomena of physiological neuronal excitability and especially in those phenomena implicated in the processes of memorisation. For example, learning has been shown to be associated with an increase in AMPA binding to its receptor in the hippocampus, one of the cerebral regions essential to mnemocognitive processes. Similarly, nootropic agents, such as aniracetam, have very recently been described as modulating positively the AMPA receptors of neuronal cells (Journal of Neurochemistry, 1992, 58, 1199-1204).
In the literature, compounds of benzamide structure have been described as having that same mechanism of action and as improving mnesic performance (Synapse, 1993, 15, 326-329). Compound BA 74, in particular, is the most active of those new pharmacological agents.
Finally, Patent Specification EP 692 484 describes a benzothiadiazine compound having a facilitatory action on the AMPA flux and Patent Application WO 99/42456 describes, inter alia, a number of benzothiadiazine compounds as AMPA receptor modulators.
In addition to being new, the benzothiadiazine compounds that are the subject-matter of the present invention, surprisingly, have pharmacological activity on the AMPA flux that is clearly superior to that of the compounds of similar structure described in the prior art. They are useful as AMPA modulators in the treatment or prevention of mnemocognitive disorders associated with age, anxiety or depression syndromes, progressive neurogenerative disorders, Alzheimer""s disease, Pick""s disease, Huntington""s chorea, schizophrenia, sequelae of acute neurodegenerative disorders, sequelae of ischaemia and with sequelae of epilepsy.
More specifically, the present invention relates to compounds of formula (I): 
wherein:
R1 represents a hydroxy, RCOxe2x80x94Oxe2x80x94 or RCOxe2x80x94NRaxe2x80x94 group,
R2 represents a hydrogen atom, a halogen atom, or a hydroxy, Rxe2x80x2COxe2x80x94O or Rxe2x80x2COxe2x80x94NRxe2x80x2axe2x80x94 group,
R and Rxe2x80x2, which may be identical or different, represent a linear or branched (C1-C6)alkyl group optionally substituted by an aryl group, a linear or branched (C2-C6)alkenyl group optionally substituted by an aryl group, a linear or branched (C1-C6)perhaloalkyl group, a (C3-C7)cycloalkyl group, an adamantyl group, an aryl group or a heteroaryl group,
Ra and Rxe2x80x2a, which may be identical or different, represent a hydrogen atom or a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)perhaloalkyl group, a linear or branched (C1-C6)acyl group, an aryl group or a heteroaryl group,
their isomers and addition salts thereof with a pharmaceutically acceptable acid or base, it being understood that:
xe2x80x9caryl groupxe2x80x9d is understood to mean a monocyclic aromatic group or a bicyclic group in which at least one of the rings is aromatic, which groups are optionally substituted by one or more, identical or different, groups selected from halogen, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)perhaloalkyl, linear or branched (C1-C6)perhaloalkoxy, hydroxy, cyano, nitro, amino (optionally substituted by one or more linear or branched (C1-C6)alkyl groups), aminosulphonyl (optionally substituted by one or more linear or branched (C1-C6)alkyl groups) and phenyl (optionally substituted by one or more, identical or different, groups selected from halogen, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)perhaloalkyl, hydroxy and linear or branched (C1-C6)alkoxy),
xe2x80x9cheteroaryl groupxe2x80x9d is understood to mean a monocyclic aromatic group or a bicyclic group in which at least one of the rings is aromatic, which groups contain one, two or three identical or different hetero atoms selected from nitrogen, oxygen and sulphur, and are optionally substituted by one or more, identical or different, groups selected from halogen, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)perhaloalkyl, linear or branched (C1-C6)perhaloalkoxy, hydroxy, cyano, nitro, amino (optionally substituted by one or more linear or branched (C1-C6)-alkyl groups) and aminosulphonyl (optionally substituted by one or more linear or branched (C1-C6)alkyl groups).
Among the pharmaceutically acceptable acids, there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, etc.
Among the pharmaceutically acceptable bases, there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The preferred aryl groups are the optionally substituted phenyl, naphthyl and tetrahydronaphthyl groups.
The preferred heteroaryl groups are the optionally substituted pyridyl, pyrrolyl, thienyl, furyl, imidazolyl and indolyl groups and more especially the groups pyridyl, thienyl and furyl.
Some preferred compounds of the invention are the compounds of formula (I) wherein R1 represents a hydroxy group and R2 represents a hydrogen or halogen atom.
Other preferred compounds of the invention are the compounds of formula (I) wherein R1 represents an RCOxe2x80x94O group and R2 represents a hydrogen atom. Among the compounds of the invention, when R1 represents an RCOxe2x80x94O group and R2 represents a hydrogen atom, the R group is preferably a (C3-C7)cycloalkyl group, an aryl group or a heteroaryl group.
The substituent R1 of the compounds of formula (I) is preferably in the 7-position.
The preferred compounds of the invention are:
5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-ol
5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl benzoate
5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl cyclohexane-carboxylate
5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl cyclobutane-carboxylate
5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl 4-methyl-benzoate
5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl 3-thiophene-carboxylate
5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl 2-thiophene-carboxylate
5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl 3-furan-carboxylate
5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl 2-furan-carboxylate
5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl nicotinate.
The invention relates also to a process for the preparation of compounds of formula (I), characterised in that there is used as starting material a compound of formula (II): 
wherein:
Rxe2x80x21 represents a linear or branched (C1-C6)alkoxy group, or a nitro group,
Rxe2x80x22 represents a hydrogen atom, a halogen atom, a linear or branched (C1-C6)alkoxy group, or a nitro group,
which is reacted with the acid chloride of formula (III) in the presence of a base, in a tetrahydrofuran or acetonitrile medium:
Clxe2x80x94(CH2)3xe2x80x94COClxe2x80x83xe2x80x83(III)
to yield a compound of formula (IV): 
wherein Rxe2x80x21 and Rxe2x80x22 are as defined hereinbefore,
which is then cyclised in a basic medium, to yield a compound of formula (V): 
wherein Rxe2x80x21, and Rxe2x80x22 are as defined hereinbefore,
which is subjected to reduction, in an alcoholic medium or in a dimethylformamide medium, in the presence of sodium borohydride, to yield a compound of formula (VI): 
wherein Rxe2x80x21 and Rxe2x80x22 are as defined hereinbefore,
which compound of formula (VI):
when Rxe2x80x21 represents a linear or branched (C1-C6)alkoxy group, is subjected to the action of boron tribromide, to yield:
either the compound of formula (I/a), a particular case of the compounds of formula (I): 
wherein Rxe2x80x32 represents a hydrogen atom, a halogen atom or a hydroxy group,
or the compound of formula (VII): 
which is then subjected to reduction, to yield the corresponding amine, which is optionally substituted, and then subjected to one or two successive acylations, to yield the compound of formula (I/b), a particular case of the compounds of formula (I): 
wherein Rxe2x80x2 and Rxe2x80x2a are as defined for formula (I),
when Rxe2x80x21 represents a nitro group, is subjected to reduction to yield the corresponding amine, which is optionally substituted, and then to an acylation, to yield the compound of formula (I/c): 
wherein R and Ra are as defined hereinbefore, and Rxe2x80x2xe2x80x32 represents a hydrogen atom, a halogen atom, a hydroxy group or an Rxe2x80x2CONRxe2x80x2a group wherein Rxe2x80x2 and Rxe2x80x2a are as defined for formula (I),
wherein the hydroxy function(s) present in the compounds of formulae (I/a), (I/b) and (I/c) may be acylated to yield the compounds (I/d) wherein the hydroxy group(s) of the phenyl ring has/have been converted to Rxe2x80x94COxe2x80x94O or Rxe2x80x2xe2x80x94COxe2x80x94Oxe2x80x94 groups wherein R and Rxe2x80x2 are as defined for formula (I),
which compounds (I/a) to (I/d) constitute the totality of the compounds of formula (I), which are purified, if necessary, according to a conventional purification technique, are separated, where appropriate, into their isomers according to a conventional separation technique, and converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base.
The invention relates also to pharmaceutical compositions comprising as active ingredient a compound of formula (I) with one or more suitable, inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragxc3xa9es, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions, etc.
The useful dosage can be adapted to the nature and severity of the disorder, the route of administration and the age and weight of the patient. The dosage varies from 1 to 500 mg per day in one or more administrations.
The following Examples illustrate the invention but do not limit it in any way.
The starting materials used are known products or are prepared according to known procedures.
The structures of the compounds described in the Examples were determined according to the usual spectrophotometric techniques (infrared, NMR, mass spectrometry, etc.).